Startle reflexes, like most motor behaviors, can be kinematically modulated in response to environmental conditions. While this modulation is disrupted in a variety of neurological disorders, the genetic bases for these disruptions in vertebrates remain poorly understood. I will focus on a gene (spaced out) isolated from a genetic screen for locomotor defects, which is specifically required for startle reflex modulation. When this gene is disrupted, individuals initiate an exaggerated and improperly coordinated response. I will uncover the neural and genetic regulation of the critical vertebrate startle response circuitry through genetic, behavioral, cell labeling, and electrophysiological approaches in zebrafish. My three specific alms are to: 1) Identify and characterize the spaced out gene, thereby identifying a genetic regulator of the vertebrate neural circuitry controlling the startle response. These experiments will reveal the temporal and spatial requirements for this critical gene during neural development and function. 2) Determine the role of the spaced out gene in startle behavior modulation, revealing the both the range and specificity of this gene's roles in regulating neuronal populations which coordinate and modulate specific motor patterns in a variety of scenarios. These experiments will test the degree of overlap in vertebrate neural circuitry regulating distinct motor behaviors. 3) Characterize the neurons modulating startle behavior that are regulated by spaced out, detailing the neural activities and patterns of synaptic connections between neural components of startle circuitry. These experiments will reveal requirements for spaced out in both the development of crucial synaptic connections and in the activity of critical neurons during startle reflexes. Completing these aims will clarify the genetic basis for the neural modulation of vertebrate startle reflex movements. PUBLIC HEALTH RELEVANCE: The startle response is a rapid, whole-body reaction to a sudden potentially threatening stimulus serving to protect individuals from a dangerous situation. My work will reveal the genetic basis for how the nervous system controls this protective behavior, and more generally how the nervous system controls coordinated movement. Understanding how these circuits work and are controlled will lead to a clearer treatment path for neurological disorders or severe nerve injuries resulting in loss of coordination.